Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.
Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.
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DOI：
10.3233/adr-170015
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发表时间：
2017-09-13
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影响因子：
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通讯作者：
Bottley A
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作者：
Boden KA;Barber IS;Clement N;Patel T;Guetta-Baranes T;Brookes KJ;Chappell S;Craigon J;Chapman NH;ARUK Consortium;Morgan K;Seymour GB;Bottley A
许多遗传位点与早发性阿尔茨海默病（EOAD）相关;然而，这种疾病的驱动因素仍然是个谜。全基因组关联和体内建模已经表明，功能丧失，例如，ABCA 7、SIRT 1和MEFF 2C水平降低或PTK 2 β水平升高可导致风险或与病原体相关。众所周知，DNA甲基化可以深刻地影响基因表达，并可以影响蛋白质组的组成;因此，本研究的目的是评估与散发性EOAD（sEOAD）相关的基因是否差异甲基化。使用焦磷酸测序平台比较从血液和皮质提取的DNA的epi谱。当与对照相比时，我们在AD血液中鉴定了位于RIN 3的3 'UTR内的7个CpG的显著组范围的低甲基化（分别为CpGl p = 0.019、CpG 2 p = 0.018、CpG 3 p = 0.012、CpG 4 p = 0.009、CpG 5 p = 0.002、CpG 6 p = 0.018和CpG 7 p = 0.013; AD/对照n = 22/26;雄性/雌性n = 27/21）。 观察到的影响没有性别特异性。在PTK 2 β、ABCA 7、SIRT 1或MEF 2C（已知与迟发性AD相关的基因）的启动子甲基化方面，未发现组间显著差异。仅在一个AD个体中观察到位于MEF 2C启动子上游的一个CpG的甲基化的罕见且显著的差异（甲基化降低22%，p = 2.0E-10;对照n = 26，AD n = 25，男性/女性n = 29/22）。 异常甲基化可能标志着血液中的sEOAD，并且可能在一些个体中表现为与sEOAD相关的基因的罕见表型变体。
A number of genetic loci associate with early onset Alzheimer’s disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2β confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3’UTR of RIN3 (CpG1 p = 0.019, CpG2 p = 0.018, CpG3 p = 0.012, CpG4 p = 0.009, CpG5 p = 0.002, CpG6 p = 0.018, and CpG7 p = 0.013, respectively; AD/Control n = 22/26; Male/Female n = 27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2β, ABCA7, SIRT1, or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, p = 2.0E-10; Control n = 26, AD n = 25, Male/Female n = 29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD.